Catalysed olefin metathesis is one of the most flexible ways in which to make carbon-carbon bonds in general and double bonds (C═C) in particular (1, 2, 3). This reaction formally cleaves two different carbon-carbon double bonds (C═C) into four fragments that are recombined with two new C═C double bonds to form olefinic products in which the original fragment partners are exchanged. The last 5-10 years have seen an almost explosive increase in the use of this reaction for the production of fine chemicals, polymers and pharmaceuticals. The reaction is catalysed and the market for metathesis catalysts is reportedly worth $1.5 bn (12.5% of the total worldwide market for catalysts) and is expanding by 9-10% annually. Despite this success, an important problem remains: The product of this transformation is in general a mixture of cis (Z) and trans (E) disubstituted isomers, with the thermodynamically more stable E-isomer usually being the major component, see FIG. 1.
The biological, chemical and physical properties within a given pair of E- and Z-isomers may, in fact, be very different, highlighting the need for selective production of single isomers. The isomer mixtures produced have to be subjected to costly separation processes. Sometimes, the separation even turns out to be impossible (4).
The catalyst is the main key to controlling the ratio with which the isomers are formed and the availability of robust and industrially compatible stereoselective catalysts is expected to expand the applicability of olefin metathesis in organic synthesis and polymerisation chemistry (3). Such catalysts would have a particular impact on the synthesis of large macrocycles by ring closing metathesis (RCM). The Z-alkene functionality is, in fact, required in many cases, either because it is present in the target molecule or because it is necessary for subsequent stereospecific transformations. A range of natural products with biological activity (e.g. anticancer, antibacterial, and antifungal) contain Z-alkene macrocyclic frameworks, see Table 1. In most of the cases, the cost of extraction of these molecules is prohibitive, and total synthesis is the only alternative (4, 5). The formation of such large rings is very challenging, with RCM standing out among the few alternative routes (1, 5, 6). Unfortunately, the lack of stereocontrol in RCM (no existing catalyst affords stereoselective RCM) constitutes a serious drawback.
Due to the lack of stereocontrol in the olefin metathesis step, alkyne metathesis (i.e., triple-bond instead of double-bond metathesis) followed by Lindlar reduction is to date the most convenient synthetic route to manufacture most of compounds in Table 1 (4, 7, 8). However, due to the commercial importance of some target products, specific procedures have been elaborated to increase the yield of the Z-isomer and improve the isolation of the product (9).
TABLE 1Representative examples of natural products to which syntheticaccess could be drastically simplified via cis-selective olefin metathesis.Natural productProperties and applicationNakadomarine AAnticancer, antifungal and antibacterialEpothilone A ($)Potent anticancerEpothilone C ($)Potent anticancerTurrianesAntineoplastic agentsMotuporamine CCytotoxic activity and/or anti-metaplasticactivity. Robust inhibitor of chick neuriteoutgrowthCruentaren AHighly cytotoxic F-ATPase inhibitorLatrunculin A ($)Actin-bindingLatrunculin B ($)Highly selective actin-bindingSophorolipid lactoneMicrobial biosurfactantEpilachnene ($)Antiinsectan activityCivetone ($)Musk odor for perfumesYuzu lactoneOlfactory moleculeAmbretolideOlfactory molecule($): commercial products
The stereochemical outcome is in general unpredictable and depends on many factors such as the nature of the substrate and of the catalyst, the reaction conditions and on the presence of specific additives (8-11). Time consuming and very costly empirical approaches are therefore required to improve the process of manufacturing the individual molecules. Hence, the quest for efficient stereoselective catalysts is to a large extent driven by commercial needs (3).
Recently, Schrock and Hoveyda have disclosed the first class of Z-stereoselective catalysts, (cf., for example, catalyst A, FIG. 2) (12-15). These new catalysts are based on molybdenum or tungsten and are capable of promoting metathesis transformations such as ring opening/cross metathesis (ROCM) (13), ring opening metathesis polymerisation (ROMP) (14), and cross-metathesis (CM) (15). However, to date, no examples of RCM have been reported. In addition, the catalysts based on molybdenum and tungsten are air and moisture sensitive and have limited functional groups tolerance. These problems are not specific to the new, stereoselective class, but are caused by the nature of the metal used and are shared by the entire family of Schrock catalysts (10). These are serious drawbacks for many industrial applications.
Several design strategies have been proposed for obtaining stereoselective ruthenium-based catalysts (catalysts B-D, cf. FIG. 2), but so far, both the selectivity and the generality resulting from these approaches have turned out disappointing (16).
U.S. Pat. Nos. 5,312,940, 5,342,909, 5,969,170, 6,111,121, 6,635,768 and 6,613,910, international patent applications WO 98/21214, WO 00/71554 and WO 2004/112951 disclose pentacoordinated ruthenium and osmium olefin metathesis catalysts. The content of those documents is herein incorporated by reference. These catalysts have the general structure:
wherein M is the metal, L and L1 are neutral ligands, R1 and R2 are H or organic moieties and X and X1 are anionic ligands.
Similarly, hexacoordinated ruthenium and osmium olefin metathesis catalysts have also been disclosed, in U.S. Pat. No. 6,818,586 and US patent application US 2003/0069374. The content of those documents is herein incorporated by reference. These catalysts have the general structure:
wherein M is the metal, L, L1 and L2 are neutral ligands, R1 and R2 are H or organic moieties and X and X1 are anionic ligands.
In both the pentacoordinated and the hexacoordinated catalysts the two anionic ligands X and X1 are preferably selected from halide and carboxylate anions. None of these catalysts, however, exhibit significant Z-stereoselectivity. U.S. Pat. No. 7,094,898 and US patent application US 2005/0131233 disclose ruthenium-based olefin metathesis catalysts with a high rate of catalytic turnover and a high degree of stability. The content of those documents is herein incorporated by reference.
The catalysts described in these documents have anionic ligands with the structure Z-Q, wherein each Z may comprise O, S, N or C and each Q comprises a planar electron-withdrawing group.
These documents also describe three novel asymmetrically substituted complexes Ru(OC6Cl5)Cl(CHPh)(IMes(py), Ru(OC6Br5)Cl(CHPh)(IMes)(py) and (Ru(OC6Br5)Cl(CHPh)(IMes)(3-Br-py) that display a weak Z-stereoselectivity in the RCM of 5-hexen-1-yl 10-undecenoate to give oxa-cyclohexadec-11-en-3-one (Exaltolide). The product obtained using these catalysts contains 9-12% more of the Z-isomer than when using a symmetrically substituted catalyst. However, the Z-stereoselectivity of these asymmetrically substituted catalysts turns out not to be general. For example, in another RCM reaction reported in the same patent, the percentage of the Z-isomer product obtained using the asymmetrically substituted catalysts Ru(OC6Cl5)Cl(CHPh)(IMes)(py) and Ru(OC6Br5)Cl(CHPh)(IMes)(py)) is very similar to that obtained using two symmetrically substituted catalysts, RuCl2(CHPh)(IMes)(py2) and Ru(OC6F5)2(CHPh)(IMes)(py).
These documents also report the only existing example of a ruthenium olefin metathesis catalyst with an anionic ligand in which a sulphur atom is bound to ruthenium (Ru(SC6F5)2(CHPh)(IMes)(py)). However, only partial characterisation, consisting of 1H-NMR and 19F NMR spectra, is provided for this compound. This catalyst displays good catalytic activity, surpassing that of the corresponding oxygen-based catalyst Ru(OC6F5)2(CHPh)(IMes)(py), for example in the RCM of the 1,9-decadiene to give cyclooctene. However, no particular E/Z stereoselectivity is reported for this catalyst.
The present invention addresses the need for active and functional group tolerant stereoselective olefin metathesis catalysts by utilising anionic ligands of very different steric requirement. In olefin metathesis reactions, the thus obtained ruthenium and osmium catalysts selectively provide the thermodynamically less favoured Z-isomers. In addition to being Z-stereoselective, these catalysts display many of the attractive properties of commonly employed ruthenium-based catalysts for olefin metathesis. In particular, preferred embodiments of the invention are highly active catalysts and are fairly stable in air and moisture. Moreover, they have already shown tolerance towards esters and are also expected to be tolerant towards a number of other functional groups.